REGULAR ARTICLE Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia Nitin Jain,1 Wendy Stock,2 Amer Zeidan,3 Ehab Atallah,4 James McCloskey,5 Leonard Heffner,6 Benjamin Tomlinson,7 Bhavana Bhatnagar,8 Jay Feingold,9 David Ungar,9 Grace Chao,9 Xiaoyan Zhang,9 Yajuan Qin,9 Karin Havenith,10 Hagop Kantarjian,1 and Matthew J. Wieduwilt11 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; 2Duchossois Center for Advanced Medicine, The University of Chicago, 3 4 Chicago, IL; Department of Hematology, Yale Cancer Center, New Haven, CT; Divison of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/3/449/1634245/advancesadv2019000767.pdf by guest on 30 April 2021 Milwaukee, WI; 5Hackensack University Medical Center, Hackensack, NJ; 6Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA; 7Department of Medicine—Hematology and Oncology, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH; 8Comprehensive Cancer Center, The Ohio State University, Columbus, OH; 9ADC Therapeutics America, Inc, Murray Hill, NJ; 10ADC Therapeutics (UK) Limited, London, United Kingdom; and 11Moores Cancer Center, University of California San Diego, La Jolla, CA Relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remains Key Points a therapeutic challenge. Loncastuximab tesirine is an antibody-drug conjugate against CD19, • Loncastuximab tesirine an antigen expressed in many B-cell malignancies. This open-label, single-arm, dose- demonstrated an escalation, dose-expansion study assessed the safety, tolerability, pharmacokinetics (PKs), acceptable safety and immunogenicity, and preliminary clinical activity of loncastuximab tesirine in adults with tolerability profile in R/R B-ALL. A total of 35 patients were enrolled, with a median age of 55 years (range, 20-80) adults with R/R and a median of 3 prior therapies (range, 1-15). All patients received at least 1 IV infusion of B-cell ALL. loncastuximab tesirine at 15 to 150 mg/kg once every 3 weeks (Q3W; n 5 30) or 50 mg/kg • Loncastuximab tesirine IV weekly (n 5 5). Common treatment-emergent adverse events (TEAEs) were nausea showed modest (42.9%), febrile neutropenia (37.1%), and reversible liver test abnormalities. Grade $3 efficacy, with 3 complete TEAEs were reported in 85.7% patients, most commonly febrile neutropenia and other responses in a heavily hematologic abnormalities and reversible liver test abnormalities. There were no pretreated R/R B-cell ALL population. treatment-related deaths. Four patients (11.4%) had grade 2 infusion-related reactions, and 1 patient (150 mg/kg Q3W) had a dose-limiting toxicity of hyperbilirubinemia that resolved within 6 days without further action. The maximum tolerated dose was not reached. Three patients achieved complete responses, 1 each at 30, 120, and 150 mg/kg Q3W. PK studies showed marked interpatient variability, with target-mediated drug disposition seeming to contribute to time- and dose-dependent disposition. No clinically relevant anti–drug- antibody formation occurred. The trial was terminated in the dose-escalation phase because of slow accrual. This trial was registered at www.clinicaltrials.gov as NCT02669264. Introduction Advances in firstline therapy for acute lymphoblastic leukemia (ALL) have led to ;80% to 90% complete response (CR) rates in adult patients with ALL with initial induction.1 Despite high initial response rates, a majority of patients eventually relapse. Outcomes for relapsed or refractory (R/R) ALL remain dismal, with survival times typically ,6 months and a CR rate of ,40% with conventional chemotherapy salvage treatments.2 Novel therapies are of increasing interest to improve treatment outcomes for patients with R/R ALL,1 and several novel agents have recently been approved for the treatment of R/R ALL of B-cell lineage (B-ALL), including blinatumomab3 (an anti-CD19 bispecific T cell–engaging antibody), Submitted 29 July 2019; accepted 18 December 2019; published online 3 February For original data, please contact [email protected]. 2020. DOI 10.1182/bloodadvances.2019000767. The full-text version of this article contains a data supplement. Presented as a poster (interim data) at the 59th annual meeting of the American © 2020 by The American Society of Hematology Society of Hematology, Atlanta, GA, 9-12 December 2017. 11 FEBRUARY 2020 x VOLUME 4, NUMBER 3 449 inotuzumab ozogamicin4 (an anti-CD22 antibody-drug conjugate of the investigator, were eligible for the study. Other key inclusion [ADC]), and tisagenlecleucel5 (an anti-CD19 chimeric antigen criteria included Eastern Cooperative Oncology Group (ECOG) receptor T-cell [CAR-T] treatment). performance status of 0 to 2 and white blood cell count ,15 3 109/L before day 1. Key exclusion criteria were known active central ADCs permit targeting of potent cytotoxic agents to cancer cells nervous system leukemia, Burkitt leukemia/lymphoma, active that express specific antigens, with the potential to maximize autoimmune disease, allogeneic stem cell transplantation within efficacy while minimizing systemic toxicities.6 The human CD19 60 days, active graft-versus-host disease, and major surgery antigen is a transmembrane glycoprotein that is expressed during or anticancer treatment within 14 days before day-1 treatment B-cell development and in B-cell lineage malignancies, including (complete inclusion/exclusion criteria are listed in the study B-ALL.7 CD19 plays a vital role in the regulation of B-cell receptor protocol included in the data supplement). signaling and is efficiently internalized upon antigen binding, making it an attractive target for antibody-based therapeutics to treat B-cell Study design and treatment malignancies. CD19 has been clinically validated as a therapeutic target with several approaches, including naked and bispecific Loncastuximab tesirine was administered IV over 60 minutes once Downloaded from http://ashpublications.org/bloodadvances/article-pdf/4/3/449/1634245/advancesadv2019000767.pdf by guest on 30 April 2021 antibodies, ADCs, and CAR-T cells.8 every 3 weeks (Q3W; day 1 of each 21-day cycle) or once weekly (QW; days 1, 8, and 15 of each 21-day cycle). If the first infusion Loncastuximab tesirine (also known as ADCT-402) is an ADC was well tolerated, the infusion duration of subsequent doses could comprising a humanized anti-CD19 antibody, stochastically conju- be shortened to 30 minutes. Patients were assigned to treatment gated through a cathepsin-cleavable valine-alanine linker to according to a 3 1 3 dose-escalation design and overseen by SG3199, a pyrrolobenzodiazepine (PBD) dimer toxin. The mech- a dose-escalation steering committee (DESC). anism of SG3199 for DNA crosslinking contributes to persistence in cells,9 and SG3199 has had picomolar antitumor activity against A hematologic dose-limiting toxicity (DLT) was defined as a grade panels of human hematologic tumor cell lines in in vitro studies.10 $3 event of neutropenia or thrombocytopenia or grade 4 anemia, with hypocellular bone marrow lasting for $6 weeks, in the absence In preclinical studies, loncastuximab tesirine has demonstrated of residual leukemia (ie, with ,5% blasts in the bone marrow). In the potent dose-dependent antitumor activity against CD19-expressing , $ 11 case of normocellular bone marrow with 5% blasts, grade 3 B-cell malignancies in both in vitro and in vivo preclinical models. pancytopenia lasting 8 weeks was considered a DLT. A non- Moreover, loncastuximab tesirine has shown an acceptable safety hematologic DLT was defined as grade 4 tumor lysis syndrome, and pharmacokinetic (PK) profile, with excellent stability and grade $3 adverse event (AE; including nausea, vomiting, diarrhea, tolerability in preclinical studies, supporting further investigation in . 11 and electrolyte imbalances lasting 48 hours despite optimal clinical trials. A first-in-human study of loncastuximab tesirine has therapy; excluding all grades of alopecia), grade $3 hypersensitivity been completed in non-Hodgkin lymphoma (NHL), and a phase 2 reaction, or grade $3 skin ulceration. The protocol-defined DLT trial has been initiated based on the high response rate in the R/R 12 observation period for dose escalation was the duration of cycle 1. diffuse large B-cell lymphoma (DLBCL) cohort. No intrapatient dose escalation was permitted. The MTD was This phase 1 trial was designed to evaluate the safety, maximum defined as the highest dose level at which none of the first 3 treated tolerated dose (MTD), PKs, immunogenicity, and preliminary clinical patients or #1 of the first 6 treated patients experienced a DLT. The activity of loncastuximab tesirine monotherapy in patients with R/R DESC determined if a Q3W or QW schedule was appropriate B-ALL in 2 parts: dose escalation (part 1) and dose expansion during dose escalation based on available safety and tolerability (part 2). The study was terminated during dose escalation because data and/or the PK profile of loncastuximab tesirine in patients. In of slow accrual. Here, we present data on all 35 patients enrolled in QW dosing, patients were administered a cumulative dose each this clinical trial. cycle comparable to the highest dose tested in Q3W without a DLT. Methods The trial was continuously monitored for safety, efficacy, and PK profile. Additional